Synergy between vancomycin and nafcillin against Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic model.

1School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, United States of America. s.leonard@neu.edu

Abstract

INTRODUCTION:

Continued pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus including heterogeneously vancomycin-intermediate S. aureus (hVISA). Infections with hVISA are associated with poor patient outcomes, thus incentivizing novel treatments. Evidence suggests that vancomycin and anti-staphylococcal penicillin susceptibility are inversely related which indicates that the use of this combination may be particularly useful against methicillin-resistant S. aureus with reduced susceptibility to vancomycin, such as hVISA. The aim of this study was to evaluate the potential for synergy between vancomycin and nafcillin against hVISA.

METHODS:

Twenty-five hVISA strains were evaluated for vancomycin and nafcillin minimum inhibitory concentration (MIC) by broth microdilution in duplicate. Potential for synergy was assessed by time-kill at 1/2x MIC in triplicate. Five strains were chosen, representing the range nafcillin MIC's available in the cohort -4, 16, 64, 128, and 256 µg/mL, and were run in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model in duplicate over 72 hours to evaluate the potential of the combination with simulated human pharmacokinetics. In addition, 4 fully glycopeptide susceptible strains of S. aureus including 2 methicillin-susceptible (MSSA) and 2 methicillin-resistant (MRSA) were run in the PK/PD model for comparison.

RESULTS:

In the time-kill, 92% of strains (23 of 25) displayed synergy with the combination of vancomycin and nafcillin. In the PK/PD model, all five strains of hVISA showed an improvement in overall activity (P≤0.004) and organism burden at 72 hours (P≤0.001) with the combination compared to either drug alone. The combination was also successful against both MRSA and MSSA in overall activity (P≤0.009) and organism burden at 72 hours (P≤0.016), though the magnitude of the effect was diminished against MSSA.

CONCLUSIONS:

The combination of vancomycin and nafcillin significantly improved antibacterial activity against hVISA, MRSA, and MSSA compared to either drug alone.

All antimicrobials are at a concentration of 0.5x MIC. This isolate shows synergy between vancomycin and nafcillin. Data are presented as a graph of the mean bacteria remaining vs. time with error bars at the sampling points representing 1 standard deviation from the mean. GC = Growth Control, NAF = Nafcillin, VAN = Vancomycin.

Activity of vancomycin and nafcillin alone and in combination in the PK/PD model against hVISA strains where the concentration of nafcillin was below the MIC of the respective organism for 100% of the dosing interval.